The intranasal route of drug administration is characterized by high bioavailability and is considered promising for rapid delivery of drugs with systemic action to the central nervous system (CNS), bypassing the blood-brain barrier. This is particularly important for the use of neuroprotective drugs in the treatment of brain tissue damage in infants caused by the effects of intrauterine hypoxia. The creation of new dosage forms for neonatology using mathematical technologies and special software in pharmaceutical development allows for the creation of cerebroprotective drugs with controlled pharmaco-technological properties, thus reducing time and resources for necessary research. We developed a new nasal gel formulation with Angiolin using a Box-Behnken experiment design for the therapy of prenatal CNS damage. It was found that the consistency characteristics of the nasal gel were significantly influenced by the gelling agent and mucoadhesive component—sodium salt of carboxymethylcellulose. We optimized the composition of nasal gel formulation with Angiolin using the formed models and relationships between the factors. The optimized nasal gel composition demonstrated satisfactory thixotropic properties. The 1% gel for neuroprotection with Angiolin, developed for intranasal administration, meets all safety requirements for this group of drug forms, showing low toxicity and no local irritant or allergic effects.

Проведены исследования структурно-механических интраназальных мягких лекарственных форм винпоцетина на эмульсионных носителях, обеспечивающих оптимальную высвобождаемость из них действующего вещества. Установлено, что реологические свойства изученных интраназальных кремов винпоцетина характеризуют их как тиксотропные системы, в структуре которых доминируют коагуляционные связи, обеспечивающие их полное восстановление после снятия напряжений, и чьи консистентные свойства полностью находятся в пределах реологического оптимума мазей. Анализ реограмм течения композиций позволил установить составы назальных эмульсионных мазей с винпоцетином, обладающих оптимальными консистентными свойствами и отобранных для дальнейшего доклинического изучения.

Aim. The study aims to develop the composition of the oromucosal gel with the IL-1β interleukin antagonist for complex treatment of inflammatory periodontal diseases. Materials and methods. Experimental studies were conducted based on the Department of Medicines Technology of Zaporizhzhia State Medical and Pharmaceutical University and the Training Medical and Laboratory Center of Zaporizhzhia State Medical and Pharmaceutical University of the Ministry of Health of Ukraine. As an active component, in the recipe of oromucosal gel, used antagonist of the interleukin IL-1B. Excipients: D-panthenol (the plasticizer), carboxymethylcellulose sodium salt (the viscosity modifier and mucoadhesive component), Tween-80 (the enhancer absorption), benzalkonium chloride (the preservative), sodium hydrophosphate + citric acid (the phosphate buffer solution), purified water. The experiments used existing and auxiliary ingredients of pharmaceutical purity, which were obtained from Sinbias LLC, Istok-Plus LLC, LLC “Mobile Medical”. For the design of the experiment, the methodology of the response surface (Box-Behnken Design) is used: Na CMC, Tween-80, D-panthenol; and four answers: pH, viscosity test, system type, mucoadhesive properties. Research methods: rheological research (viscosity test, amplitude test, frequency test, mucoadhesive test, thixotropy test) performed in oscillation mode on the modular compact Rheometer Anton Paar MCR 302 (CP50-1 SN71317), which, compared to cylindrical devices, requires a much smaller amount of gel sample and allows the planned tests in the oscillation mode, the temperature in the experiments was provided with a built-in thermostat (Peltier Temperature Control, C-PTD 200). Pharmaco-toxicological studies were conducted on 46 white outbred rats of both sexes, weighing 160–180 grams, which were received from Vivarium by the Institute of Pharmacology and Toxicology. The studies were performed on enough animals, all manipulations were carried out by the provisions on the use of animals in biomedical experiments. The results of the study were calculated using the standard statistical package of the Statistica for Windows 13 (StatSoft Inc., No. JPZ804I382130ARCN10-J), as well as SPSS 16.0, Microsoft Office Excel 2003. Results. According to the design of the experiment, it is established that the components of the system do not change the value of pH in experimental oromucosal gels (6.5500 ± 0.0334). The Anova for Quadratic Model statistical analysis data certify the significant impact of Na CMC, and Tween-80 factors on the viscous characteristics of oromucosal gels (F-value > p-value). Comparison of mucoadhesive characteristics of the studied samples of oromucosal gels was made using dynamic mechanical analysis and the results of statistical analysis of ANOVA for Quadratic Model highlight the significant influence of Na CMC, D-panthenol, Tween-80. Optimized oromucosal gel test data is obtained that its structure is restored after the applied effort, namely the restoration of the structure after 10 seconds occurs by 69.5 %, after 30 s by 76.1 %, after 180 s by 85.4 %, after 180 s which allows to predict the stability of the dosage form, both after manufacture and after use. Conclusions. The composition of the oromucosal gel of anti-inflammatory action with the IL-1β interleukin antagonist for the complex treatment of inflammatory diseases of periodontal is developed. The optimized composition of the oromucosal gel obtained has satisfactory performance of kinetic stability and thixotropic properties. The developed gel for dentistry meets all the requirements for harmlessness and safety for dosage forms of this group toxicity, lack of local irritant and allergic action.

In the development of new effective and safe drugs an important place is occupied by the issue of ensuring the stability of the dosage form. In this case, a significant contribution to this problem is made directly by the nature of the active pharmaceutical ingredient. Based on our experimental studies, the composition of the base-carrier of the nasal drug with the receptor antagonist intereleukin-1 (IL-1ra) was determined, and the need to add a preservative was identified. However, focusing on the peptide nature of the biologically active component of IL-1ra, it is necessary to take into account the possible lack of stability during storage of the drug with changes in pH. The aim of the work is to optimize the composition of a nasal drug with an interleukin antagonist (IL-1ra) to increase its storage stability. As the active pharmaceutical ingredient used a semi-finished solution of the receptor antagonist of interleukin-1 (IL-1ra). Excipients were: sodium carboxymethylcellulose, tween-80, D-panthenol, trilon B, benzalkonium chloride. To ensure the appropriate pH value used phosphate buffer solutions, which were prepared according to State Pharmacopoeia. The study of some indicators of pharmaceutical availability (kinetic indicators) was performed by studying the release of the active ingredient from the drug composition by equilibrium dialysis in purified water. Equilibrium dialysis was performed through Cuprofan cellophane film at 37 ± 0.5 °C in Franz Diffusion Cell System. The content of IL-1ra in the dialysate was determined spectrophotometrically, at certain intervals. As a result of pharmaco-technological studies to optimize the composition of the nasal agent with IL-1ra, it was found that the developed nasal agent with IL-1ra requires the addition of stabilizers to the composition of the formulation. It was found that the use as stabilizers: phosphate buffer solution 6.0 and trilon B, provides proper release of the active substance from the dosage form and corrects the stability of the hydrogen index over time. The obtained results of pharmaceutical availability indicators indicate that the release of IL-1ra from the nasal form is subject to the first order equation.

Сучасний розвиток біофармацевтичних досліджень у світовій науці та практиці сприяє використанню нових лікарських форм або шляхів введення діючих речовин в організм людини. Увагу дослідників привертає застосування неінвазивних шляхів введення лікарських засобів, що можуть бути використані як для нових лікарських субстанцій, так і для чинних. Неінвазивні шляхи введення препаратів мають деякі переваги перед інвазивними: не пошкоджують шкірний покрив, не потребують спеціальної кваліфікації та умов застосування лікарських засобів, забезпечують належний рівень терапевтичної ефективності лікарських засобів. Одним із таких шляхів введення активнодіючих речовин в організм людини є інтраназальний шлях. За останні десятиліття вчені отримали позитивні результати щодо використання інтраназального шляху для системного застосування. Назальні лікарські засоби для системного застосування легко застосовувати, вони не викликають подразнення шлунково-кишкового тракту людини. Під час інтраназального введення діючі речовини потрапляють відразу в загальний кровообіг і на відміну від ентерального шляху минають пресистемну елімінацію, що запобігає передчасному руйнуванню препарату. Мета роботи – маркетингове дослідження вітчизняного ринку зареєстрованих інтраназальних лікарських засобів для місцевого та системного застосування. Матеріали та методи. Як матеріал дослідження використовували офіційні дані Державного реєстру лікарських засобів України з деталізацією до форми випуску препарату, дозування, виробника, країни-виробника, фармакотерапевтичної групи. Результати. Згідно з даними Державного реєстру лікарських засобів на вітчизняному ринку зареєстровано 226 інтраназальних лікарських препаратів. Висновки. Здійснили маркетингове дослідження вітчизняного ринку інтраназальних лікарських засобів для місцевого та системного застосування. Встановили, що серед зареєстрованих інтраназальних препаратів переважна більшість – 94,7% – для місцевого застосування. Частка системних інтраназальних засобів становить тільки 5,3%. Аналіз конкурентоспроможності показав, що найбільша конкуренція спостерігається в інтраназальних місцевих засобів, практично відсутня конкуренція в інтраназальних системних.

In order to save resource of active pharmaceutical ingredients and excipients, in the early stages of research, when planning an experiment, it is advisable to use data of the predicted and experimental physicochemical properties stored in different aggregation databases. The information found will reduce the time for composition development and for technology processing. However, the variety of active compounds characteristics and excipients is not always reflected in these services. Recently, machine learning models have been widely used in various scientific fields; they allow to obtain predictions with high reliability. Given the above, it is relevant and promising to develop models of machine learning to predict the presence of pharmaceutical incompatibilities in the formulation of nasal dosage forms. The aim of the study is to develop models of machine learning for in silico forecast of the rational composition of nasal dosage forms with cerebroprotective action. Materials and methods. A dataset, containing data on compounds (active and auxiliary) and characteristics on the presence or absence of interaction (pharmaceutical incompatibility), was used as material. Training datasets were filled by content analysis of PubMed library data (pubmed.ncbi.nlm.nih.gov) manually, by keywords “pharmaceutical incompatibilities”, “physico-chemical compatibility”, “incompatible excipients”) for the last 10 years. The resulting dataset comprises 1185 lines. The methods employed were a set of methods for binary classification of machine learning (pycaret.org) using the programming language Python 3.8 (python.org) in the package management environment Miniconda (conda.io). Pipeline programming was performed using Jupyter notebook package (jupyter.org). The generation of MACCS (Molecular ACCess System keys) in the training dataset was performed using RDKit package (rdkit.org). Specifications of the simplified representation of molecules in the input line (SMILES), in automatic mode, were searched using PubChem service (pubchem.ncbi.nlm.nih.gov). Results. The obtained data allowed to choose two perspective models of machine learning of binary classification, whose quality was checked on a dataset for verification. Statistical evaluations of the selected models indicate a high probability of in silico prognosis for the presence or absence of pharmaceutical incompatibilities in the development of nasal formulations of cerebroprotective dosage forms. They are posted on the web server of the expert system ExpSys Nasalia (nasalia.zsmu.zp.ua) in the calculations section. Conclusions. As a result of our research, we have developed machine learning models for in silico prediction of the rational composition of nasal dosage forms with cerebroprotective action. Confirmation of the quality of the pharmaceutical incompatibilities prediction, using the developed models, is checked on a dataset for check. The statistical indicators of the tree_blender (AUC 0.9521, F1 0.9747, MCC 0.9094) and boost_blender (AUC 0.9593, F1 0.9821, MCC 0.9352) models were obtained. The use of machine learning models in pharmaceutical development will contribute to resource conservation and optimization of the composition of the formulation.